Cyclopropanyl-bearing hydrazides

ABSTRACT

Cyclopropanyl-group-bearing-hydrazides, e.g. cis-2-octyl-cyclopropanoctanoic acid, 2-(o-methylphenyl)-hydrazide, are useful as pharmaceutical agents and are obtainable by reacting a derivative, e.g. mixed anhydride, of a cyclopropanyl-group bearing-long chain carboxylic acid with an appropriate hydrazine.

This is a continuation-in-part of copending application Ser. No. 881,781filed Feb. 27, 1978 now abandoned.

This invention relates to organic compounds and more particularly tocyclopropanyl-group bearing-hydrazides (and pharmaceutically acceptableacid addition salts thereof) and to pharmaceutical compositionscontaining such compounds, as well as to the pharmaceutical use of suchcompounds.

The compounds of this invention are conveniently represented by theformula I: ##STR1## wherein A is an ethylenically unsaturated fatty acidhydrocarbon chain of 7 to 23 carbon atoms in which each unsaturatedethylene moiety, ie. of the formula:

    --CH═CH--

is replaced by a cyclopropanyl group of the formula ##STR2## said Ahaving 1 to 4 such cyclopropanyl groups (and said A hence being asaturated chain): and

R is:

(a) an aralkyl radical of the structure ##STR3## wherein g is 0 or 1;wherein

R¹ is a hydrogen atom, halo having an atomic weight of from about 19 to80, ie. fluoro, chloro or bromo, alkoxy having from 1 to 3 carbon atoms,eg methoxy; or alkyl having from 1 to 3 carbon atoms, eg methyl;

R² is a hydrogen atom, alkyl having from 1 to 3 carbon atoms, alkoxyhaving from 1 to 3 carbon atoms, or halo having an atomic weight of fromabout 19 to 36, ie fluoro or chloro; and

R³ is i) a hydrogen atom, a phenyl radical of the structure ii) ##STR4##wherein y is a hydrogen atom, halo having an atomic weight of from about19 to 80, ie. fluoro, chloro or bromo, alkoxy having from 1 to 3 carbonatoms, eg methoxy; or alkyl having from 1 to 3 carbon atoms, eg methyl;and

y' is a hydrogen atom, alkoxy having from 1 to 3 carbon atoms, alkylhaving from 1 to 3 carbon atoms, or halo having an atomic weight of fromabout 19 to 36, ie fluoro or chloro; or a benzyl radical of the formulaiii) ##STR5## wherein y and y' are as defined above; or iv) alkyl havingfrom 1 to 8 carbon atoms; or R is:

(b) a phenyl radical of the structure ##STR6## wherein R² is as definedabove, and R° is a hydrogen atom, halo having an atomic weight of fromabout 19 to 80, ie fluoro, chloro or bromo, alkyl having from 1 to 3carbon atoms; alkoxy having from 1 to 3 carbon atoms; or a radical ofthe structure R^(f) : ##STR7## in which B is --CH₂ -- or --O--;

f is 0 or 1; and

Q is a hydrogen atom, halo having an atomic weight of from about 19 to80, alkoxy having from 1 to 3 carbon atoms, or alkyl having from 1 to 3carbon atoms;

or R is:

(c) an indolyl radical of the structure: ##STR8## wherein R¹ is asdefined above, and R⁵ is a hydrogen atom, alkyl having from 1 to 8carbon atoms or benzyl (unsubstituted);

or R is

(d) a benzocycloalkyl nucleus of the structure: ##STR9## wherein R¹ andR² are as defined above; and j is a whole integer of from 1 to 4.

Compounds I may be obtained by acylation (process a) of a hydrazine offormula II:

    II H.sub.2 N - NH-R

in which R, is as defined above, with a cyclopropanyl-bearing-fatty acidor derivative thereof corresponding to the moiety -A as defined above.Such "acylation" may be carried out by means conventionally employed inconverting a hydrazino function to its corresponding hydrazide, such asare reported in the literature.

The acylation (process a) may conveniently be carried out by a mixedanhydride technique (process a1) wherein a compound II is treated with amixed anhydride of the formula III: ##STR10## in which A is as definedabove and R⁶ is a lower unbranched alkyl having from 1 to 6 carbonatoms, at moderate temperatures, eg from about -10° C. to +35° C., in aninert organic medium, eg a chlorinated hydrocarbon, such as methylenechloride.

The mixed anhydrides (III) are obtainable by reacting (process b1) afree carboxylic acid of the formula IV: ##STR11## wherein A is asdefined above, with a chloroformate of the formula V, ##STR12## whereinR⁶ is as defined above, in the presence of an acid acceptor, eg anorganic base, such as triethylamine, at reduced temperatures, eg at fromabout -10° to +30° C., in an inert organic medium, eg a chlorinatedhydrocarbon, such as methylene chloride.

Another convenient method of preparing compounds I comprises reacting(process a2) an acyl halide of the formula VI ##STR13## in which A is asdefined above, and X is either chloro or bromo, with a compound II (asdefined above), in the presence of an acid acceptor, in an inert mediumat moderate temperatures, eg from about 10° to 50° C. preferably atabout 20° to 30° C.

The acyl halides (VI) may be prepared in the conventional manner, eg bytreating (process b2) a corresponding compound IV (as defined above),with a halogenating agent capable of contributing a chlorine or bromineatom, eg thionyl chloride (or - bromide, as appropriate).

In the above-described processes, neither the media nor the temperatureare critical to the reactions, and where the reactants or reagents areliquid, an excess thereof may serve as the reaction medium. If desired acompound II may be in the form of a water-soluble acid addition salt,for example the hydrochloride. The mixed anhydride (III) resulting fromprocess b1) may conveniently be used in situ. That is to say thatprovided that the materials in the reaction mixture containing the mixedanhydride are not detrimental, they may be used directly for process a1)without recovery.

Reagents and reactants described herein, e.g., compounds II, III, IV, V,and VI are known and obtainable by known means, or where not known, maybe obtained by adaptation of methods reported in the literature for thepreparation of known analogs; many such compounds being commerciallyavailable.

With respect to R, when it is of type (a) or (b) and R° is not R^(f), itis preferred that when R¹, R° or y is other than a hydrogen atom and R²(or y') is a hydrogen atom, that R°, or R¹, or y be located at the2-position; and that when R² (or y') is also other than a hydrogen atomthat R¹ or R° and R² (or y and y') are the same, and it is additionallypreferred that they be located at the 2- and 6-positions on the phenylring. When R is of type (a) where g=1, and R³ is of type (iii), then Rcan be an α-(benzyl)-phenylethyl radical.

With particular respect to the substituent R° when it is a radicalR^(f), it will be appreciated that when B=CH₂ and f=1, then the radicalR^(f) is of the benzyl type. When B=oxygen and f=1, then the radicalR^(f) is of the phenoxy-type. When f=zero, then the radical R^(f) is ofthe phenyl-type. Hence, when R is of type (b) and R° is of type R^(f)where f=zero, then R can be a biphenylyl radical. The radical R^(f) ispreferably at the para-position. When Q is other than a hydrogen atom,it is preferably at the para-position.

With respect to R, when it is of type (c), it is preferred that when R¹is other than a hydrogen atom, it be located at the 5-position of theindole nucleus.

With respect to R when it is of type (d) it is preferred that when R¹ isother than a hydrogen atom, that it be located at a carbon atom ortho tothe ring junction; and that when R² is also other than a hydrogen, it ispreferred that it be the same as R¹, and it is additionally preferredthat it be in para-relationship to R¹. It is additionally preferred thatthe amide group be linked to a carbon of the cycloalkyl moiety which isdirectly bonded to a ring junction carbon. It is also preferred that jbe 1, ie, that the benzocycloalkyl nucleus be indanyl, and particularly1-indanyl.

In the above-presented definitions, when R°, R¹ or y is halo, it ispreferably fluoro or chloro, and particularly chloro; and when R² or y'is halo it is preferably chloro.

Cyclopropanyl group-bearing fatty acids (IV) are conveniently obtainedby converting the ethylenically unsaturated positions of correspondinglong chain unsaturated fatty acids to cyclopropanyl groups. It will beappreciated that each olefinic unit: --CH═CH-- is thus replaced by acyclopropanyl unit: ##STR14## Since each cyclopropanyl unit contributesan additional carbon atom to the linear portion of the hydrocarbonradical A, the total number of carbon atoms in A will equal the numberof carbon atoms in the linear portion plus the total number ofcyclopropanyl units thereon.

For example, compounds suitable as cyclopropanyl-bearing acids (IV) (ortheir derivatives) are obtainable by treatment of a corresponding mono-or poly-unsaturated long chain fatty acid (VII) with methyleneiodide(CH₂ I₂) by the Simmons-Smith method (described in J.A.C.S. 81, 4256(1959).

For preparing compounds IV bearing a single cyclopropanyl unit, thestarting acids (VII) may possess either the cis-oid or trans-oidconfiguration. When acids with cis-oid configuration are used, theSimmons-Smith reaction, used for preparing the corresponding"cyclopropane" acids (IV), leads only to cis "cyclopropane" acids, andsimilarly the trans-acids gives the corresponding trans-"cyclopropane"acids. Mixtures will of course lead to corresponding mixture. When acyclopropane acid is reacted with an appropriate hydrazine, H₂ N-NHR(II), which carries any asymmetric carbon atoms, to give the hydrazide(I), it will be appreciated that the resulting hydrazide (I) is obtainedas a mixture of diastereoisomers, which may be separated, through knownrecovery methods, such as chromatography and crystallization.Alternatively, if desired, the starting cyclopropane acid may beresolved into its antipodes, and a particular antipode then reacted withthe desired optical isomer of an amine (II), to give the correspondingisomeric product is relatively pure isomeric form.

Similarly, for preparing cyclopropane acids (IV) bearing two or morecyclopropanyl units, the starting olefinic acids have a correspondingnumber of double bonds, and the Simmons-Smith reaction leads to amixture of diastereomeric acids, which may be separated before reactingwith the appropriate hydrazide (II).

Since compounds I having only one cyclopropanyl unit have a lessernumber of asymmetric carbon atoms than those derived from acid ofgreater unsaturation, they are generally easier to refine and aretherefore, preferred from that standpoint, where ease of purification isan important factor in their preparation.

In general it is preferred that A is unbranched. It is further preferredthat each pair of hydrogen atoms bound to the tertiary carbon atoms ofeach cyclopropanyl group is in the cis configuration.

A preferred class of Compounds I are those wherein A is acyclopropanyl-bearing hydrocarbon radical of the formula A1: ##STR15##wherein n is a whole integer of from 1 to 15; m is 1 or 2; and p is awhole integer of from 1 to 13, provided that when m is 1, then n+p isfrom 3 to 19, and when m is 2 then n+p is from 2 to 16; and particularlythose having in addition to the various preferences discussed above, oneor more of the following characteristics with respect to the A-moiety:(1) n+p=7 to 19 when m is 1; or n+p=4 to 16 when m=2; (2) n+p=an oddnumber when m=1, and an even number when m=2; and (3) when m=1, then n=5or 7 and p=6; and when m=2, then n=4 and p=6.

In view of the above-presented preferences it will be appreciated thatit is particularly preferred that in compounds I the A-moiety is derivedfrom mono- or di-unsaturated fatty acids (or esters thereof) of the typefound in nature, especially palmitoleic or oleic acid (m=1); andlinoleic acid (m=2).

Particular embodiments of this invention are the compoundcis-2-octyl-cyclopropanoctanoic acid, 2-(o-methylphenyl)hydrazide, andpharmaceutical compositions containing said compound, as well as the useof said compound and compositions containing said compound as describedherein.

Additional particular embodiments of this invention are the compoundcis-2-octyl-cyclopropanoctanoic acid,2-[α-(p-methylbenzyl)-p-methyl-phenylethyl]-hydrazide of Example 5, andpharmaceutical compositions containing said compound, as well as the useof said compound and compositions containing said compound as describedherein.

The final products and intermediate compounds described herein may berecovered and refined, where such is desired, by conventional means,such as by crystallization, distillation or chromatographic techniquessuch as column or thin layer chromatography.

STATEMENT OF UTILITY

The compounds of formula I of this invention are useful aspharmaceutical agents in animals. In particular, the compounds of theformula I are useful in controlling the cholesterol ester content ofmammalian arterial walls and are therefore particularly indicated foruse as antiatherosclerotic agents, ie. agents useful in the prophylactictreatment of atherosclerois and in the controlling of atheroscleroticconditions due to cholesterol ester accumulation in the arterial walls.Such ability of the compounds of the formula I is indicated by knowntest procedures in which the total cholesterol ester content of culturedcells is shown to be reduced by a test compound, as compared tountreated cells, and carried out, for example, by the followingprocedures:

(A) Cell culture

Rhesus monkey smooth muscle cells (from the arterial, eg aorta, wall)obtained by the method of K. Fisher-Dzoga et al (Experimental andMolecular Pathology 18, 162-176 (1973)) are routinely grown in 75 cm²tissue culture flasks using Minimum Essential Medium (Eagle)supplemented with 10% fetal bovine serum. For testing a 75 cm² flaskwith a near cofluent cell growth is selected. The cells are removed fromthe flask surface by mild enzymatic treatment with pronase. Aftercentrifugation and decanting the enzyme solution, the cell pellet isresuspended in an appropriate volume of media for seeding the desirednumber of 60 mm tissue culture dishes. Five (5) ml of the diluted cellsuspension are pipetted into each dish. After seeding, the dishes arelabelled with the cell type, date and flask number of origin andincubated at 37° C. in approximately 5% CO₂ atmosphere in a highhumidity incubator. When the cultures are confluent, the actual drugtesting is begun. Test compounds are routinely solubilized in 100%ethanol. An equivalent amount of ethanol is added to control groups aswell. The tissue culture dishes are randomly divided into groups. To onegroup, hyperlipemic rabbit serum (HRS) is added at 5% by volume(control). To the remaining groups, 5% HRS and 1 mg per 100 ml of mediaof the test compound are added. The dishes are returned to the incubatorfor an additional 24 hours. All operations through to the finalincubation are performed using sterile technique in a laminar flow hood.After the incubation period, the dishes are microscopically observedwith the Zeiss Axiomat with phase contrast optics and the conditions ofthe cultures are recorded; especially in regard to the size, number andconfiguration of cytoplasmic inclusions and to cellular morphology. Themedia is removed from the cultures and 0.9% sodium chloride solution isadded. The cells are removed from the flasks with the aid of a rubberpoliceman and transferred to a conical graduated centrifuge tube. Thecells are washed three times by suspending in an isotonic salt solution,centrifuging at 800× g for 10 minutes and aspirating the supernatantfluid.

(B) Cell extraction procedure

An appropriate volume of isopropyl alcohol (about 1 ml/mg protein) isthen added to the cell pellet and the sample sonicated with a microprobe (140×3 mm) for 10 seconds with a "LO" setting of 50 on a BronwellBiosonik IV. After centrifugation for 15 minutes at 800× g, the clearsupernatant is decanted and an aliquot taken for cholesterol analysis.

The residue is dissolved in 0.1 N sodium hydroxide and an aliquot takenfor protein determination by the method of Lowry, et al. (J. Biol. Chem.193, 265; 1951).

(C) Assay

Free cholesterol: The isopropyl alcoholic solutions of standards,samples and blank (isopropyl alcohol alone) are treated in a similarmanner. An aliquot of 0.4 ml of free reagent (Reagent A, Table 1 below)is added to a 10×75 mm disposable glass test tube to which 20 μl of theisopropyl alcoholic solution is added and mixed. After standing at roomtemperature for approximately 5 minutes, 0.8 ml of 0.5 N sodiumhydroxide (Reagent C, Table 1) is added and mixed. The fluorescence ismeasured with an Aminco-Bowman spectrophotofluorometer with anexcitation wavelength of 325 nm and emission wavelength of 415 nm. A 1cm light path cuvette is used with a xenon lamp, an IP28 photomultipliertube and 2 mm slits.

Total cholesterol: The same procedure described above for freecholesterol is followed for total cholesterol except that the totalreagent (Reagent B, Table 1) is used instead of the free reagent and thesamples are incubated for 20 minutes at 37° C. before the addition ofthe 0.5 N sodium hydroxide solution (Reagent C, Table 1).

Alternatively, the assay for cholesterol, ie Step C (above) obtainedfrom Steps A and B, may be carried out by the method of Ishikawa et al(J. Lipid Res. 15, 286; 1974).

The amount of cholesterol ester is found by subtracting the amount offree cholesterol from the total cholesterol content of the cellsdetermined by the assay. A finding of a lower amount of cholesterolester in the group of cells to which test compound was added, ascompared to the control group (untreated) shows that the test compoundis active in reducing the cholesterol ester in the cells.

                  Table 1                                                         ______________________________________                                        Composition of Reagents for                                                   Cholesterol Determination                                                     A.     Free Cholesterol Reagent                                                      Sodium phosphate buffer pH 7.0                                                                     .05     M                                                Cholesterol oxidase  .08     U/ml                                             Horseradish peroxidase                                                                             30.     U/ml                                             p-Hydroxyphenylacetic acid                                                                         .15     mg/ml                                     B.     Total Cholesterol Reagent                                                     Sodium phosphate buffer pH 7.0                                                                     .05     M                                                Cholesterol ester hydrolase                                                                        .08     U/ml                                             Cholesterol oxidase  .08     U/ml                                             Horseradish peroxidase                                                                             30.     U/ml                                             Sodium tamochlolate  5.      mM                                               Carbowax-6000        .17     mM                                               p-Hydroxyphenylacetic acid                                                                         .15     mg/ml                                     C.     Sodium Hydroxide Solution                                                                          .5N                                               ______________________________________                                    

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, suspensionscontaining, for example, from about 0.5 to 5% of suspending agent,syrups containing, for example, from about 10 to 50% of sugar, andelixirs containing, for example, from about 20 to 50% ethanol, and thelike, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5 to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

Furthermore, the compounds of formula I may be similarly administered inthe form of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the free base with an appropriate acidand accordingly are included within the scope of the invention.Representative of such salts are the mineral acid salts, such as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts such as the benzoate, acetate, maleate, fumarate,p-toluenesulfonate, benzenesulfonate and the like.

The antiatherosclerotic effective dosage of active ingredient employedfor the reduction of cholesterol ester content in the arterial walls ofa mammal may vary depending on the particular compound employed, themode of administration and the severity of the condition being treated.However, in general, satisfactory results are obtained when thecompounds of formula I are administered at a daily dosage of from about2 milligrams to about 500 milligrams per kilogram of animal body weight,preferably given in divided doses two to four times a day, or insustained release form. For most large mammals, the total daily dosageis from about 100 milligrams to about 5,000 milligrams preferably fromabout 100 milligrams to 2,000 milligrams. Dosage forms suitable forinternal use comprise from about 25 to 2,500 milligrams of the activecompound in intimate admixture with a solid or liquid pharmaceuticallyacceptable carrier. Solid carriers include starch, lactose and kaolin,while liquid carriers include sterile water, polyethylene glycols andedible oils such as corn, peanut and sesame oils, as are appropriate tothe nature of the active ingredient and the particular form ofadministration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded, such as flavoring agents, coloring agents, preserving agents,and antioxidants eg vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the stand-point of easeof preparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationis preferred.

A representative formulation for administration orally three times a dayprior to feeding in the treatment of atherosclerosis is a gelatincapsule prepared by conventional techniques to contain the following

    ______________________________________                                        Ingredient              Weight (in Mg.)                                       ______________________________________                                         cis-2-octyl-cyclopropanoctanoic                                                                      300    300    300                                     acid, 2-(o-methylphenyl hydrazide).                                           corn oil                500    200    --                                      lactose                 --     --     200                                     ______________________________________                                    

As is the present understanding in the art, controlling the totalcholesterol content of an arterial wall by inhibiting the accumulationthereof by reducing the cholesterol ester content thereof,advantageously inhibits the formation of plaques in the arterial wall.

Where NMR characterization data is presented, the analysis is run inCDCl₃ and values given in ppm; digits in parenthesis are number ofprotons; and b=broad, d=doublet and s=singlet.

The following examples are illustrative of the invention. Alltemperatures are centigrade and room temperature is 20 to 30° C., unlessindicated otherwise.

EXAMPLE 1 cis-2-Octyl-cyclopropanoctanoic acid,2-(o-methylphenyl)-hydrazide ##STR16##

To a solution of 3.0 g of dihydrosterculic acid* in 75 ml methylenechloride cooled to -20°, is added dropwise 1.1 g triethyl amine and thendropwise 1.1 g ethyl chloroformate. The reaction mixture is allowedgradually to come to room temperature and stirred for 2 hours. There isthen added 1.0 g triethylamine followed by 1.6 g o-methylphenylhydrazine hydrochloride and the reaction mixture then stirred for 16hours. Thereafter the reaction mixture is extracted five times withportions of 2 N hydrochloric acid, then once with 2 N aqueous sodiumhydroxide and washed extensively with saturated aqueous sodium chloride.The organic phase is then dried over anh. sodium sulphate, filtered andthe filtrate evaporated i.v. to dryness to obtain a residue. The residueis then chromatographed over silica gel, with chloroform as the eluent.The desired fractions** are combined and evaporated i.v. to dryness toyield the title product as a waxy solid, NMR; b +0.65(3), b -0.3(1), d8.0(1), d 6.1(1), s 2.1(3).

EXAMPLE 2

Repeating the procedure of Example 1, but using in place of theo-methylphenyl-hydrazine used (as a compound II) therein, anapproximately equivalent amount of:

(a) 1-indanyl-hydrazine

(b) β-(3-indolylethyl)-hydrazine;

(c) (d,l) α-methylbenzyl-hydrazine (racemate);

(d) 2-chlorophenyl hydrazine;

(e) α-(p-methylbenzyl)-benzyl hydrazine; or

(f) benzylhydrazine dihydrochloride; there is accordingly obtained,respectively:

(a) cis-2-octyl-cyclopropanoctanoic acid, 2-(1-indanyl)-hydrazide;

(b) cis-2-octyl-cyclopropanoctanoic acid,2-[β-(3-indolylethyl)[-hydrazide

(c) cis-2-octyl-cyclopropanoctanoic acid, 2-(α-methylbenzyl)-hydrazide(mixture of racemates);

(d) cis-2-octyl-cyclopropanoctanoic acid, 2-(o-chlorophenyl)-hydrazide;

(e) cis-2-octyl-cyclopropanoctanoic acid,2-[α-(p-methylbenzyl)-benzyl]-hydrazide; and

(f) cis-2-octyl-cyclopropanoctanoic acid, 2-benzylhydrazide as a wax,NMR: b +0.6(3), b -0.3(1), d -, s 4.7(2).

EXAMPLE 3

Repeating the procedure of Example 1, but using in place of thedihydrosterulic acid used (as a compound IV) therein, an approximatelyequivalent amount of:

(a) 2-hexylcyclopropanoctanoic acid;

(b) trans-2-octylcyclopropanoctanoic acid; or

(c) cis-2-tetradecylcyclopropanobutyric acid; there is accordinglyobtained

(a) cis-2-hexyl-cyclopropanoctanoic acid, 2-(o-methylphenyl)-hydrazide

(b) trans-2-octyl-cyclopropanoctanoic acid,2-(o-methylphenyl)-hydrazide;

(c) cis-2-tetradecylcyclopropano butanoic acid,2-(o-methylphenyl)-hydrazide.

EXAMPLE 4 cis,cis-2-[(2-pentylcyclopropyl)-methyl]-cyclopropanoctanoicacid 2-(o-methylphenyl)-hydrazide ##STR17##

Repeating the procedure of Example 1, but using in place of thedihydrosterculic acid used therein, an approximately equivalent amountof cis,cis-2-[(2-pentylcyclopropyl)-methyl]-cyclopropanoctanoic acidthere is accordingly obtained the title product as an oil (mixture ofdiastereoisomers), NMR: b +0.65(6), b -0.3(2), d 7.8(1) d 6.1(1), s2.1(3).

EXAMPLE 5 cis-2-octyl-cyclopropanoctanoic acid,2-[α-(p-methylbenzyl)p-methyl-phenylethyl]-hydrazide* ##STR18##

Repeating the procedure of Example 1, but using in place of theo-methylphenyl hydrazine (as compound II) used therein, an approximatelyequivalent amount of α-(p-methylbenzyl)-p-methylphenylethyl-hydrazinethere is accordingly obtained the title product.

EXAMPLE 6

Repeating the procedure of Example 2, but using an approximatelyequivalent amount ofcis,cis-2-[2-(pentylcyclopropyl)-methyl]-cyclopropanoctanoic acid inplace of the dihydrosterculic acid used in each portion therein, theanalogous cis,cis-2-[(2-pentylcyclopropyl)-methyl]-cyclopropanoctanoicacid-hydrazides of the products named therein are accordingly obtained.

What is claimed is:
 1. A compound of the formula: ##STR19## wherein A isa saturated hydrocarbon chain interrupted by from 1 to 4 cyclopropanylgroups of the formula ##STR20## said A being of from 7 to 23 carbonatoms plus one additional carbon atom for each cyclopropanyl group; andRis: (a) an aralkyl radical of the structure ##STR21## wherein g is 0 or1; wherein R¹ is a hydrogen atom, halo having an atomic weight of fromabout 19 to 80, alkoxy having from 1 to 3 carbon atoms; or alkyl havingfrom 1 to 3 carbon atoms; R² is a hydrogen atom, alkyl having from 1 to3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, or halo havingan atomic weight of from about 19 to 36; and R³ is (i) a hydrogen atom,a phenyl radical of the structure (ii) ##STR22## wherein y is a hydrogenatom, halo having an atomic weight of from about 19 to 80, alkoxy havingfrom 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms; andy' is a hydrogen atom, alkoxy having from 1 to 3 carbon atoms, alkylhaving from 1 to 3 carbon atoms, or halo having an atomic weight of fromabout 19 to 36; ora benzyl radical of the formula (iii) ##STR23##wherein y and y' are as defined above; or (iv) alkyl having from 1 to 8carbon atoms; or R is: (b) a phenyl radical of the structure ##STR24##wherein R² is as defined above, and R° is a hydrogen atom, halo havingan atomic weight of from about 19 to 80, alkyl having from 1 to 3 carbonatoms; alkoxy having from 1 to 3 carbon atoms; or a radical of thestructure R^(f) : ##STR25## in which B is --CH₂ -- or --O--; f is 0 or1; and Q is a hydrogen atom, halo having an atomic weight of from about19 to 80, alkoxy having from 1 to 3 carbon atoms, or alkyl having from 1to 3 carbon atoms;or R is: (c) an indolyl radical of the structure:##STR26## wherein R¹ is as defined above, and R⁵ is a hydrogen atom,alkyl having from 1 to 8 carbon atoms or benzyl (unsubstituted);or R is(d) a benzocycloalkyl nucleus of the structure: ##STR27## wherein R¹ andR² are as defined above; and j is a whole integer of from 1 to
 4. 2. Acompound of claim 1 in which R is a type (a).
 3. A compound of claim 1in which R is of type (b).
 4. A compound of claim 1 in which R is oftype (c).
 5. A compound of claim 1 in which R is of type (d).
 6. Acompound of claim 2 in which g is
 0. 7. A compound of claim 2 in which gis
 1. 8. A compound of claim 2 in which R³ is of type (iii).
 9. Acompound of claim 3 in which R¹ is a radical of the structure ##STR28##in which B, f and Q are as defined.
 10. A compound of claim 1 wherein Ais a cyclopropanyl-bearing hydrocarbon radical of the formula: ##STR29##wherein n is a whole integer of from 1 to 15; m is 1 or 2; and p is awhole integer of from 1 to 13, provided that when m is 1, then n+p isfrom 3 to 19, and when m is 2 then n+p is from 2 to
 16. 11. A compoundof claim 10 in which m is
 1. 12. A compound of claim 10 in which m is 2.13. A compound of claim 11 in which n is 7 and p is
 6. 14. The compoundof claim 13 which is cis-2-octylcyclopropanoctanoic acid,2-(o-methylphenyl)hydrazide.
 15. The compound of claim 13 which iscis-2-octylcyclopropanoctanoic acid,2-[α-(p-methylbenzyl)-p-methylphenylethyl]hydrazide.
 16. A compound ofclaim 12 in which n is 4 and p is
 6. 17. The compound of claim 16 whichis cis,cis-2-[(2-pentylcyclopropyl)-methyl]-cyclopropanoctanoic acid,2-(o-methylphenyl)hydrazide.
 18. A compound of claim 10 in which thehydrogen atoms of each cyclopropanyl group are in the cis configuration.19. A method of reducing the cholesterol ester content of an arterialwall, in a mammal in need of such treatment, comprising administering acholesterol ester-reducing amount of a compound of claim 1 to saidmammal.
 20. A pharmaceutical composition suitable for reducing thecholesterol ester content of an arterial wall of a mammal comprising acholesterol ester-reducing effective amount of a compound of claim 1 anda nontoxic pharmaceutically-acceptable carrier.
 21. A composition ofclaim 20 in solid form.
 22. A composition of claim 20, in which thecompound is present in an amount of from about 25 to 2,500 milligrams.23. A composition of claim 22 in which the compound iscis-2-octyl-cyclopropanoctanoic acid, 2-(o-methylphenyl)-hydrazide. 24.A method of claim 19 in which the compound iscis-2-octyl-cyclopropanoctanoic acid, 2-(o-methylphenyl)-hydrazide. 25.A composition of claim 22 in which the compound iscis-2-octyl-cyclopropanoctanoic acid,2-[N-α-(p-methylbenzyl)-p-methyl-phenylethyl]-hydrazide.
 26. A method ofclaim 19 in which the compound is cis-2-octyl-cyclopropanoctanoic acid,2-[N-α-(p-methylbenzyl)-p-methyl-phenylethyl]-hydrazide.
 27. Thecompound of claim 13 which is cis-2-octyl-cyclopropanoic acid,2-benzyl-hydrazide.